1. Field of the Invention
The present invention relates to a novel solubilizing composition, its liquid and powder formulations, its liquid and powder formulations containing pharmaceutical compounds, and the preparation method thereof wherein said solubilizing composition comprises 9˜90% by weight of at least one selected from the monoglycerides, 0.01˜90% by weight, of at least one emulsifier, and 0˜90.9% by weight of an organic solvent.
2. Description of the Related Art
Solubilization of materials can be applied to a variety of fields. In chemical processing where their catalysts, reactants, intermediates, etc. are water-insoluble materials, the solubilization of these materials will affect the yield and the direction of a given reaction. Numerous pharmaceutical compounds with good physiological activities are known to be insoluble in water and thus they have relatively low bioavailabilities. Because the solubilization of these pharmaceutical compounds can simplify administration routes and increase pharmaceutical effects, the solubilization technology is essential in commercializing water-insoluble pharmaceuticals, and therefore extensive worldwide studies have been focused on developing the solubilization technology. Cyclosporin and paclitaxel (Taxol®), for instance, are good Examples of water-insoluble pharmaceutical compounds that cannot be administered alone due to their low solubilities. The solubilizing technology, therefore, has been developed simultaneously with the development of these pharmaceutical compounds themselves. Cyclosporin and paclitaxel are commercially available as pre-concentrates of Cremophor emulsion. These formulations can spontaneously form microemulsion upon dispersion in water (U.S. Pat. No. 5,438,072).
In general, solubilizing formulations include emulsion or liposome, which uses lipid as a medium, and a polymeric nanoparticle or polymeric micelle, which uses a polymer as a medium (Langer, R. Nature, 392, 5-10, 1998). Of these, the formulations using lipid as a medium are relatively advantageous in that their raw materials are biocompatible and thus they can be widely applied to medical fields including drug delivery systems. In particular, the emulsions are heterogeneous mixture of oil and water by the use of emulsifiers. The oil-in-water type emulsions, composed of oil components dispersed in water, are widely used in solubilizing water-insoluble pharmaceutical compounds. Liposome formulations consist of spherical lipid vesicles with lipid bilayers and water-insoluble pharmaceutical compounds are enclosed within the lipid bilayer.
U.S. Pat. No. 5,531,925 discloses Cubosome, another type of formulation using lipid as a solubilization medium, which was first developed by Swedish scientists in early 1990s. Cubosome is prepared by dispersing the hydrated lipid cubic phase in water. The interior of Cubosome comprises cubic phase wherein lipid and water components constitute continuous but separate three-dimensional channels, and there exists an interface between lipid headgroup and water. Therefore, Cubosome could be advantageous over the conventional emulsion type or liposome type formulations, which only allow solubilization of hydrophobic and hydrophilic pharmaceutical compounds, respectively, in that they can solubilize amphiphilic pharmaceutical compounds as well as hydrophobic and hydrophilic pharmaceutical compounds.
Cubosomes can be formed by first forming a very viscous liquid cubic phase by adding water and an emulsifier to monoglyceride, and then by dispersing the mixture in water. Cubosome has average particle size of as large as several micrometers in diameter with the aid of emulsifiers. Since it is preferential to have submicron-sized particles for the solubilization of pharmaceutical compounds, it is also possible to obtain submicron-sized particles by applying mechanical forces such as microfluidization.
Preparing submicron-sized cubosome particles by means of a mechanical force, however, may result in physicochemical instability of the enclosed materials or the constituting ingredients of the formulations due to high energy and high temperature accompanying the mechanical process. The formulation process may also incur hydrolysis and oxidization of constituting ingredients because the enclosed materials or the constituting ingredients of the formulations may be vigorously mixed with air during the microfluidization process. Moreover, the dispersed cubosomes prepared by the microfluidization process may experience the instability of the dispersion system after a prolonged storage and subsequently result in phase separation due to aggregation of particles. Although cubosome type formulations have adventageous properties as described above over the conventional type of formulations, they also have disadvantages that they cannot encapsulate the thermally labile pharmaceutical compounds. Also, the physical and chemical stability of the formulation need to be improved greatly to provide a successful drug delivery system.